The KCNE2 single transmembrane domain protein regulates multiple types of cardiac voltage-gated potassium (Kv) channel in vivo and its disruption causes the ventricular arrhythmia, Long QT Syndrome. Interestingly, a SNP near the human KCNE2 locus was also previously linked to early-onset myocardial infarction (MI). Because KCNE2 is also expressed outside the heart, we are interested in understanding extracardiac defects caused by Kcne2 deletion in mice, and also the potential contribution of these extracardiac defects to cardiac dysfunction. Thus, recently, we found that Kcne2 deletion creates a multifactorial substrate for sudden cardiac death (SCD) that includes diabetes mellitus and dyslipidemia. Because atherosclerosis is the most common cause of MI, here, using Kcne2-/- mice, we investigated atherosclerosis and other potential predisposing factors in MI and SCD, and quantified the impact of a Western diet (high fat/high cholesterol) on these processes. Previously, we discovered impaired glucose tolerance in adult Kcne2-/- mice using a standard glucose tolerance assay in which plasma glucose is quantified 0-2 hours following glucose injection. Here, we found that in Kcne2-/- mice as young as 5 weeks, just 2 weeks on a Western diet induced impaired glucose tolerance, whereas 5-week-old wild-type mice regardless of diet, or Kcne2-/- mice on a control diet, had normal glucose tolerance. This indicates a strong interaction between diet and Kcne2 deletion in creating early-onset diabetes mellitus. Atherosclerosis was also investigated, using Sudan IV staining of plaques in the aorta of wild-type and Kcne2-/- mice fed on either standard (control) or Western diet. Strikingly, Kcne2-/- mice as young as 4.5 months exhibited aortic plaques, and this was accelerated by a Western diet. In contrast, wild-type littermates did not exhibit plaques at this age, regardless of diet. Ongoing studies to determine potential metabolic defects in the liver and pancreas are aimed at understanding the molecular mechanisms underlying these findings. Our data provide further evidence of the unexpected complexity of monogenic cardiovascular syndromes caused by disruption of genes associated with cardiac arrhythmias.